Composition for creating vascular occlusions

ABSTRACT

A composition including 2-hexyl cyanoacrylate and goal is useful in treating arteriovenous malformations (AVMs) and other body lumens to be blocked.

This application is a reissue of Ser. No. 09/159,621, filed Sep. 11,1998, now U.S. Pat. No. 6,032,366, which claims the benefit of U.S.Provisional Application No. 60/058,510, filed on Sep. 11, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a composition used to treat arteriovenousmalformations (“AVMs”) and other vascular abnormalities. The compositionincludes a cyanoacrylate liquid monomer and gold in a prepolymerizedpolymer of cyanoacrylate. The composition is placed into the body lumenvia standard catheter procedures or directly percutaneously.

2. Description of the Related Art

AVMs and vascular tumors, especially those of the brain, are exceedinglydifficult to treat. These growths may occur all over the body, but areespecially difficult to treat when in the brain or brain stem. Thecomposition of the invention is especially useful in treatingneurological AVMs, but may also be used to treat tumors anywhere in thebody.

Cyanoacrylate adhesives have been used surgically but are limited intheir usefulness by cytotoxicity and heat generation. The brain isunusually sensitive to cytotoxicity and heat.

The art described in this section is not intended to constitute anadmission that any patent, publication or other information referred toherein is “prior art” with respect to this invention, unlessspecifically designated as such. In addition, this section should not beconstrued to mean that a search has been made or that no other pertinentinformation as defined in 37 C.F.R. § 1.56(a) exists.

SUMMARY OF THE INVENTION

The invention provides a composition that may be placed in a body lumenincluding veins and arteries by super selective catheterization ordirect puncture using standard tools of the interventional angiographer.The composition of the invention has been successfully tested insimulated models of the AVMs and tumors under fluoroscopy and in systemsthat closely resembles the neurological condition of the human body.Further studies have been done in the pig rete. The rete is a body offine arteries that allows the blood to flow into the pig brain whichclosely resembles normal human AVMs.

The composition is a cyanoacrylate which involves mixing two separatecontainers of the material immediately prior to administration of thematerial into the AVM by catheter. The composition may contain seveningredients which are divided into two parts prior to mixture and use.It furnishes properties that are useful for closing neurological AVMs.The product can also be used to close any growth resembling an AVM inany part of the body. Because of the sensitive nature of the tissues inthe brain, the general sensitivity of the product must be controlled. Inless sensitive areas, the product will work equally as well.

Part I consists of a cyanoacrylate liquid monomer containing purephosphoric acid (250 ppm) hydroquinone (100 ppm) and P-methoxyphenol(1200 ppm). This composition is stable and unchanging we believe forover two years. The container in which Part I is stored requirescleaning and preparation before such stability can be achieved. Theliquid monomer of choice for this usage is 2-hexyl cyanoacrylate.

Part II consists of pure powdered gold (5×3 microns), a small amount ofprepolymerized polymer of the same cyanoacrylate and ethyl myristate.Any of the large chain fatty acid esters will work to replace ethylmyristate so long as they are liquids.

The pre-polymerized polymers of cyanoacrylate are unstable and changetheir structures and properties even in the solid state. The change isexponential and therefore the polymer must be used within a limitedamount of time before deterioration occurs.

The polymer is prepared by addition of part 1 to a rapidly stirring weakbicarbonate-water solution. The addition must be added drop-wise toavoid unpolymerized masses from forming. The solid polymer is washedthoroughly with pure water to remove any traces of bicarbonate, thenwashed thoroughly with pure methanol to remove the water. Methanol driesrapidly and when the polymer is further dried at a high reduced pressurefor 16-18 hours, it is considered dry. The polymer must be used in thenext step within 24 hours to obtain consistent results in the finalproduct. This mixture must be sterilized within 72 hours from the timeof preparation.

Part II is sterilized with ethylene oxide gas with the stopper held inan open position. Ethylene oxide is an alkylating agent and aftersterilization the prepolymerized polymer is stable. Hence, the stabilityand sterilization of part 2 are carried out simultaneously. Thesterilized samples of Part II are capped in a clean room under sterilehandling conditions.

The pre-polymerized polymer can be stabled by treatment with any of thestrong alkylating agents, like ethylene oxide, ketone, etc.

This composition of matter has good cohesion as well as adequateadhesion to function well for AVMs and other similar uses within thevascular tree. The cohesion keeps the material together during the timerequired for it to polymerize. The adhesion makes it stick to the arterywalls.

The polymerized device will cause a modest but desirable inflammatoryresponse in the treated tissues.

A Formulation for Arteriovenous Malformations and Tumors

It is desirable to prepare a formulation for the intravascular occlusionof AVMs and Tumors that will have the following properties:

-   -   The product has a very slow rate of biodegradation.    -   Both liquid and solid forms should have excellent cohesion.    -   The delivered product should have medium adhesion    -   The delivered product must be radiopaque.    -   The solid polymer should be soft and pliable.    -   The delivered product must have a very low or negligible        histotoxicity.    -   The deposited product must have no long term negative properties        such as carcinogenicity, teratogenicity, systemic toxicity or        other unpredictable biological and medical effects.    -   The products must be sterile.    -   The delivered product must have good few characteristics for        selective catheterization.    -   The product must be stable on storage for an extended period of        time.    -   The formulation should be made from pure products and be        reproducible for simple manufacturing procedures.        The product formulation is:

Part I (M1) 2-Hexyl Cyanoacrylate 999,550 ppm Hydroquinone 100 ppmp-Methoxyphenol 100 ppm Pure Phosphoric Acid 250 ppm Part II (M2) PureGold 1.0000 g Pure Ethyl Myristate 0.5000 g FMS* 0.0200 g *FMS is aspecially prepared polymer of 2-hexyl cyanoacrylate and must be usedwithin 24 hours of preparation or will change and be unusable. Further,it must be sterilized within 72 hours.

Each item of this formulation is critical to the proper performance ofthe product.

2-Hexyl Cyanoacrylate

This cyanoacrylate homolog was chosen because it biodegrades very slowlyin blood or any living tissue. The secondary alcohol will biodegradeseveral thousand times slower than its primary derivative. This veryslow degradation rate also lowers greatly the histotoxicity.

Hydroquinone

When the amount of hydroquinone is reduced by half (50 ppm) the productshows low shelf life stability. Large amounts over 100 ppm do not seemto effect the product stability. This inhibitor lowers the effect of thehigh energy free radicals that may appear in the cyanoacrylate.

p-Methoxyphenol

The slow polymerization of cyanoacrylates even under refrigeration iscaused by low energy free radicals. When 100 ppm of p-methoxyphenol ispresent this slow polymerization is prevented and long term stability isachieved. Less p-methoxyphenol (50 ppm) will not protect the product.

Sulfur Dioxide

The faintest trace of sulfur dioxide is present in the product. One partper million can be seen and less is present. However, this very fainttrace adds to the stability of Neuracryl* ml in the ampule.

Gold

Tantalum, platinum and gold are all radiopaque. Gold was best for usbecause it could be suspended colloidally in the mixture. One gram ofgold is used per device.

Ethyl Myristate

Subbicates, fatty acid esters and other plasticizers, are useful forfastening the polymers of the cyanoacrylates. they also will stabilizethe pre-formed polymers of the cyanoacrylates so that they may be usedas thickeners. We have chosen ethyl myristate, an esterified,biocompatible fatty acid because of the convenience of purification andanalysis and because is works well to give the formulation the desirableproperties.

FMS

FMS is the polymer of 2-hexyl cyanoacrylate formed in a weak, aqueoussodium bicarbonate solutions. The polymer diners in structure and sizedepending on how it is formed. This polymer will remain stable until M2can be formulated. The polymer must be formed and dried completelybefore use. The final formulation of M2 must occur within 24 hoursbecause the ethyl myristate stabilized FMS until sterilization can beperformed. After sterilization the product is stable for several years.

Neuracryl M

M1 and M2 are mixed immediately before use. The mixture should he usedwithin 4 hours after mixing. If there is a delay, the syringe should beturned over several times a minute to resuspend the gold which will besettled.

1. A composition for creating therapeutic vascular occlusions in ananimal comprising a mixture of: (a) Part 1 comprised of 2-hexylcyanoacrylate, hydroquinone, p-methoxyphenol and phosphoric acid; and(b) Part 2 comprising gold metal powder, ethyl myristate and asterilized a large chain fatty acid ester in liquid form and astabilized polymer of 2-hexylcyanoacrylate in weak aqueous bicarbonatesolution .
 2. The composition of claim 1 wherein Part 1 comprises about100 PPM hydroquinone, 100 PPM p-methoxyphenol, 250 PPM phosphoric acidand the remainder 2-hexyl cyanoacrylate.
 3. The composition of claim 2wherein Part 2 comprises about 65 percent by weight gold, about 30percent by weight ethyl myristate and the remainder said sterilizedstabilized polymer of 2-hexylcyanoacrylate in weak aqueous bicarbonatesolut ion .
 4. The composition of claim 1 wherein Part 2 includes sulfurdioxide as a stabilizer.
 5. A method for creating therapeutic vascularocclusions in an animal needing therapeutic vascular occlusioncomprising the steps of: (a) Mixing together Part 1 comprised of 2-hexylcyanoacrylate, hydroquinone, p-methoxyphenol and phosphoric acid withPart 2 comprising gold metal powder, ethyl myristate and a sterilized alarge chain fatty acid ester in liquid form, and a stabilized polymer of2-hexylcyanoacrylate in weak aqueous bicarbonate solution ; and (b)injecting administrating the mixture into a vascular site needingocclusion with the gold metal powder suspended in the mixture .